Pharmacopeial Forum 1260 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]
BRIEFING the general principles involved in the manufacture of some of them, particularly on a small scale. Other information that is gi- ven bears on the use of the Pharmacopeial substances in extem- h1151i Pharmaceutical Dosage Forms, USP 32 page poraneous compounding of dosage forms. 663. This general information chapter is being revised in its en- tirety to represent current compendial thinking with respect to official preparations. The proposed revision incorporates con- BIOAVAILABILITY cepts outlined in a Stimuli to the Revision Process article, Devel- opment of a Compendial Taxonomy and Glossary for Bioavailability, or the extent to which the therapeutic constit- Pharmaceutical Dosage Forms, authored by an Ad Hoc Commit- uent of a pharmaceutical dosage form intended for oral or top- tee composed of the chairs of the Pharmaceutical Dosage ical use is available for absorption, is influenced by a variety of Forms Expert Committee, Biopharmaceutics Expert Commit- factors. Among the inherent factors known to affect absorption tee, Nomenclature and Labeling Expert Committee, and the are the method of manufacture or method of compounding; Council of Experts for the revision cycle, 2000—2005, and pub- the particle size and crystal form or polymorph of the drug sub- lished in PF 29(5). The Stimuli article proposed a tiered catego- stance; and the diluents and excipients used in formulating the rization for pharmaceutical dosage forms proceeding from dosage form, including fillers, binders, disintegrating agents, route of administration to physical form and ultimately release lubricants, coatings, solvents, suspending agents, and dyes. Lu- pattern. This proposed general information chapter emphasizes bricants and coatings are foremost among these. The mainte- the second tier of the compendial taxonomy, the physical dos- nance of a demonstrably high degree of bioavailability requires age form, rather than the route of administration, with the in- particular attention to all aspects of production and quality con- tention of avoiding redundancy for dosage forms given by trol that may affect the nature of the finished dosage form. multiple routes. The proposed revision is organized into four sections provid- ing discussion of general considerations, product quality tests, TERMINOLOGY dosage form monographs, and a glossary. General considera- tions include dose uniformity, stability, bioavailability, manufac- Occasionally it is necessary to add solvent to the contents of a ture, and route of administration. The discussion of product container just prior to use, usually because of instability of some quality tests reflects the universally applied as well as dosage drugs in the diluted form. Thus, a solid diluted to yield a suspen- form specific testing that help assure safety and efficacy from sion is called [DRUG] for Suspension; a solid dissolved and dilu- manufacture through shelf life. The dosage form monographs ted to yield a solution is called [DRUG] for Solution; and a provide general descriptions, discussion of general principles of solution or suspension diluted to yield a more dilute form of their manufacturing or compounding, and recommendations the drug is called [DRUG] Oral Concentrate. After dilution, it is for proper use and storage. The glossary is intended to provide important that the drug be homogeneously dispersed before guidance in selection of official names for official articles but administration. also as a resource to provide definitions beyond those used in official names for dosage forms.Theglossaryclearlydistin- guishes preferred from not preferred terminology. AEROSOLS The revised general information chapter presents current concepts relating to the naming of dosage forms. Outdated Pharmaceutical aerosols are products that are packaged un- forms such as elixirs, spirits, tinctures, and syrups are herein re- der pressure and contain therapeutically active ingredients that cognized as solutions. Lotions are defined as emulsions typically are released upon activation of an appropriate valve system. for topical use. While inserts are defined as solid dosage forms They are intended for topical application to the skin as well as for placement within body cavities, suppositories are differenti- local application into the nose (nasal aerosols), mouth (lingual ated as only for placement within the rectum. aerosols), or lungs (inhalation aerosols). These products may be This general information chapter is intended to be supple- fitted with valves enabling either continuous or metered-dose mented by more detailed discussion of characteristics, quality delivery; hence, the terms ‘‘[DRUG] Metered Topical Aerosols,’’ tests, and other considerations based on route of administra- ‘‘[DRUG] Metered Nasal Aerosols,’’ etc. tion. Early drafts of such concepts relating to topical and trans- The term ‘‘aerosol’’ refers to the fine mist of spray that results dermal dosage forms are presented in PF 35(3) [May–June from most pressurized systems. However, the term has been 2009]. Proposed general test chapter h3i Topical and Transder- broadly misapplied to all self-contained pressurized products, mal Drug Products—Product Quality Tests, providing quality test- some of which deliver foams or semisolid fluids. In the case of ing procedures, complements the performance testing Inhalation Aerosols, the particle size of the delivered medication proposed in h725i Topical and Transdermal Drug Products— must be carefully controlled, and the average size of the parti- Product Performance Tests. Additional revision proposals of sim- cles should be under 5 mm. These products are also known as ilar standards for the oral (gastro-intestinal), mucosal, by inha- metered-dose inhalers (MDIs). Other aerosol sprays may con- lation, and by injection routes are planned. tain particles up to several hundred micrometers in diameter. The basic components of an aerosol system are the container, (BPC: W. Brown.) RTS—C69686 the propellant, the concentrate containing the active ingredi- ent(s), the valve, and the actuator. The nature of these compo- nents determines such characteristics as particle size distribution, uniformity of dose for metered valves, delivery rate, wetness and temperature of the spray, spray pattern and Change to read: velocity or plume geometry, foam density, and fluid viscosity.
Types of Aerosols h1151i PHARMACEUTICAL Aerosols consist of two-phase (gas and liquid) or three-phase (gas, liquid, and solid or liquid) systems. The two-phase aerosol DOSAGE FORMS consists of a solution of active ingredients in liquefied propel- lant and the vaporized propellant. The solvent is composed of the propellant or a mixture of the propellant and cosolvents Dosage forms are provided for most of the Pharmacopeial such as alcohol, propylene glycol, and polyethylene glycols, drug substances, but the processes for the preparation of many which are often used to enhance the solubility of the active in- of them are, in general, beyond the scope of the Pharmacopeia. gredients. In addition to defining the dosage forms, this section presents In-Process Revision
# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1261
Three-phase systems consist of a suspension or emulsion of Containers the active ingredient(s) in addition to the vaporized propel- lants. A suspension consists of the active ingredient(s) that Aerosol containers usually are made of glass, plastic, or metal, may be dispersed in the propellant system with the aid of suit- or a combination of these materials. Glass containers must be able excipients such as wetting agents and/or solid carriers such precisely engineered to provide the maximum in pressure safe- as talc or colloidal silicas. ty and impact resistance. Plastics may be employed to coat A foam aerosol is an emulsion containing one or more active glass containers for improved safety characteristics, or to coat ingredients, surfactants, aqueous or nonaqueous liquids, and metal containers to improve corrosion resistance and enhance the propellants. If the propellant is in the internal (discontinu- stability of the formulation. Suitable metals include stainless ous) phase (i.e., of the oil-in-water type), a stable foam is dis- steel, aluminum, and tin-plated steel. Extractables or leachables charged; and if the propellant is in the external (continuous) (e.g., drawing oils, cleaning agents, etc.) and particulates on phase (i.e., of the water-in-oil type), a spray or a quick-breaking the internal surfaces of containers should be controlled. foam is discharged. Manufacture Propellants Aerosols are usually prepared by one of two general proces- The propellant supplies the necessary pressure within an aer- ses. In the ‘‘cold-fill’’ process, the concentrate (generally cooled osol system to expel material from the container and, in com- to a temperature below 08) and the refrigerated propellant are bination with other components, to convert the material into measured into open containers (usually chilled). The valve-actu- the desired physical form. Propellants may be broadly classified ator assembly is then crimped onto the container to form a as liquefied or compressed gases having vapor pressures gener- pressure-tight seal. During the interval between propellant ad- ally exceeding atmospheric pressure. Propellants within this dition and crimping, sufficient volatilization of propellant oc- definition include various hydrocarbons, especially halogenat- curs to displace air from the container. In the ‘‘pressure-fill’’ ed derivatives of methane, ethane, and propane, low molecular method, the concentrate is placed in the container, and either weight hydrocarbons such as the butanes and pentanes, and the propellant is forced under pressure through the valve orifice compressed gases such as carbon dioxide, nitrogen, and ni- after the valve is sealed, or the propellant is allowed to flow un- trous oxide. Mixtures of propellants are frequently used to ob- der the valve cap and then the valve assembly is sealed (‘‘under- tain desirable pressure, delivery, and spray characteristics. A the-cap’’ filling). In both cases of the ‘‘pressure-fill’’ method, good propellant system should have the proper vapor pressure provision must be made for evacuation of air by means of vac- characteristics consistent with the other aerosol components. uum or displacement with a small amount of propellant vapor. Manufacturing process controls usually include monitoring of proper formulation and propellant fill weight and pressure test- Valves ing, leak testing, and valve function testing of the finished aer- osol. Microbiological attributes should also be controlled. The primary function of the valve is to regulate the flow of the therapeutic agent and propellant from the container. The spray characteristics of the aerosol are influenced by orifice dimen- Extractable Substances sion, number, and location. Most aerosol valves provide for continuous spray operation and are used on most topical prod- Since pressurized inhalers and aerosols are normally formulat- ucts. However, pharmaceutical products for oral or nasal inha- ed with organic solvents as the propellant or the vehicle, leach- lation often utilize metered-dose valves that must deliver a ing of extractables from the elastomeric and plastic uniform quantity of spray upon each valve activation. The accu- components into the formulation is a potentially serious prob- racy and reproducibility of the doses delivered from metering lem. Thus, the composition and the quality of materials used in valves are generally good, comparing favorably to the uniformi- the manufacture of the valve components (e.g., stem, gaskets, ty of solid dosage forms such as tablets and capsules. However, housing, etc.) must be carefully selected and controlled. Their when aerosol packages are stored improperly, or when they compatibility with formulation components should be well es- have not been used for long periods of time, valves must be tablished so as to prevent distortion of the valve components primed before use. Materials used for the manufacture of valves and to minimize changes in the medication delivery, leak rate, should be inert to the formulations used. Plastic, rubber, alumi- and impurity profile of the drug product over time. The extract- num, and stainless steel valve components are commonly used. able profiles of a representative sample of each of the elasto- Metered-dose valves must deliver an accurate dose within spec- meric and plastic components of the valve should be ified tolerances. established under specified conditions and should be correlated to the extractable profile of the aged drug product or placebo, to ensure reproducible quality and purity of the drug product. Actuators Extractables, which may include polynuclear aromatics, nitrosa- mines, vulcanization accelerators, antioxidants, plasticizers, An actuator is the fitting attached to an aerosol valve stem, monomers, etc., should be identified and minimized wherever which when depressed or moved, opens the valve, and directs possible. the spray containing the drug preparation to the desired area. Specifications and limits for individual and total extractables The actuator usually indicates the direction in which the prep- from different valve components may require the use of differ- aration is dispensed and protects the hand or finger from the ent analytical methods. In addition, the standard USP biological refrigerant effects of the propellant. Actuators incorporate an testing (see the general test chapters Biological Reactivity Tests, orifice that may vary widely in size and shape. The size of this In Vitro h87i and Biological Reactivity Tests, In Vivo h88i) as well as orifice, the expansion chamber design, and the nature of the other safety data may be needed. propellant and formulation influence the delivered dose as well as the physical characteristics of the spray, foam, or stream of solid particles dispensed. For inhalation aerosols, an actuator Labeling capable of delivering the medication in the proper particle size Revision In-Process range and with the appropriate spray pattern and plume geom- Medicinal aerosols should contain at least the following etry is utilized. warning information on the label as in accordance with appro- priate regulations. Warning—Avoid inhaling. Avoid spraying into eyes or onto other mucous membranes.
# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1262 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]
NOTE—The statement ‘‘Avoid inhaling’’ is not necessary for tins having relatively high gel strength. Either type may be preparations specifically designed for use by inhalation. The used, but blends of pork skin and bone gelatin are often used phrase ‘‘or other mucous membranes’’ is not necessary for pre- to optimize shell clarity and toughness. Hard-shell capsules also parations specifically designed for use on mucous membranes. may be formed from starch or other suitable substances. Hard- Warning—Contents under pressure. Do not puncture or in- shell capsules may also contain colorants, such as D&C and cinerate container. Do not expose to heat or store at tempera- FD&C dyes or the various iron oxides, opaquing agents such tures above 1208 F (498 C). Keep out of reach of children. as titanium dioxide, dispersing agents, hardening agents such In addition to the aforementioned warnings, the label of a as sucrose, and preservatives. They normally contain between drug packaged in an aerosol container in which the propellant 10% and 15% water. consists in whole or in part of a halocarbon or hydrocarbon Hard gelatin capsules are made by a process that involves shall, where required under regulations of the FDA, bear either dipping shaped pins into gelatin solutions, after which the gel- of the following warnings: atin films are dried, trimmed, and removed from the pins, and Warning—Do not inhale directly; deliberate inhalation of the body and cap pieces are joined. Starch capsules are made contents can cause death. by injection molding a mixture of starch and water, after which the capsules are dried. A separate mold is used for caps and bo- Warning—Use only as directed; intentional misuse by deliber- dies, and the two parts are supplied separately. The empty cap- ately concentrating and inhaling the contents can be harmful sules should be stored in tight containers until they are filled. or fatal. Since gelatin is of animal origin and starch is of vegetable origin, capsules made with these materials should be protected from potential sources of microbial contamination. BOLUSES Hard-shell capsules typically are filled with powder, beads, or granules. Inert sugar beads (nonpareils) may be coated with ac- Boluses are large elongated tablets intended for administra- tive ingredients and coating compositions that provide extend- tion to animals (see Tablets). ed-release profiles or enteric properties. Alternatively, larger- dose active ingredients themselves may be suitably formed into pellets and then coated. Semisolids or liquids also may be filled CAPSULES into hard-shell capsules; however, when the latter are encapsu- lated, one of the sealing techniques must be employed to pre- Capsules are solid dosage forms in which the drug is enclosed vent leakage. within either a hard or soft soluble container or ‘‘shell.’’ The In hard gelatin capsule filling operations, the body and cap of shells are usually formed from gelatin; however, they also may the shell are separated prior to dosing. In hard starch shell filling be made from starch or other suitable substances. Hard-shell operations, the bodies and caps are supplied separately and are capsule sizes range from No. 5, the smallest, to No. 000, which fed into separate hoppers of the filling machine. Machines em- is the largest, except for veterinary sizes. However, size No. ploying various dosing principles may be employed to fill pow- 00 generally is the largest size acceptable to patients. Size 0 ders into hard-shell capsules; however, most fully automatic hard gelatin capsules having an elongated body (known as size machines form powder plugs by compression and eject them OE) also are available, which provide greater fill capacity with- into empty capsule bodies. Accessories to these machines gen- outanincreaseindiameter.Hardgelatincapsulesconsistof erally are available for the other types of fills. Powder formula- two, telescoping cap and body pieces. Generally, there are tions often require adding fillers, lubricants, and glidants to the unique grooves or indentations molded into the cap and body active ingredients to facilitate encapsulation. The formulation, portions to provide a positive closure when fully engaged, as well as the method of filling, particularly the degree of com- which helps prevent the accidental separation of the filled cap- paction, may influence the rate of drug release. The addition of sules during shipping and handling. Positive closure also may wetting agents to the powder mass is common where the ac- be affected by spot fusion (‘‘welding’’) of the cap and body tive ingredient is hydrophobic. Disintegrants also may be in- pieces together through direct thermal means or by application cluded in powder formulations to facilitate deaggregation of ultrasonic energy. Factory-filled hard gelatin capsules may be and dispersal of capsule plugs in the gut. Powder formulations completely sealed by banding, a process in which one or more often may be produced by dry blending; however, bulky formu- layers of gelatin are applied over the seam of the cap and body, lations may require densification by roll compaction or other or by a liquid fusion process wherein the filled capsules are wet- suitable granulation techniques. ted with a hydroalcoholic solution that penetrates into the Powder mixtures that tend to liquefy may be dispensed in space where the cap overlaps the body, and then dried. hard-shell capsules if an absorbent such as magnesium carbo- Hard-shell capsules made from starch consist of two, fitted nate, colloidal silicon dioxide, or other suitable substance is cap and body pieces. Since the two pieces do not telescope used. Potent drugs are often mixed with an inert diluent before or interlock positively, they are sealed together at the time of being filled into capsules. Where two mutually incompatible filling to prevent their separation. Starch capsules are sealed drugs are prescribed together, it is sometimes possible to place by the application of a hydroalcoholic solution to the recessed one in a small capsule and then enclose it with the second drug section of the cap immediately prior to its being placed onto in a larger capsule. Incompatible drugs also can be separated by the body. placing coated pellets or tablets, or soft-shell capsules of one The banding of hard-shell gelatin capsules or the liquid seal- drug into the capsule shell before adding the second drug. ing of hard-shell starch capsules enhances consumer safety by Thixotropic semisolids may be formed by gelling liquid drugs making the capsules difficult to open without causing visible, or vehicles with colloidal silicas or powdered high molecular obvious damage, and may improve the stability of contents weight polyethylene glycols. Various waxy or fatty compounds by limiting O2 penetration. Industrially filled hard-shell capsules may be used to prepare semisolid matrices by fusion. also are often of distinctive color and shape or are otherwise Soft-shell capsules made from gelatin (sometimes called soft- marked to identify them with the manufacturer. Additionally, gels) or other suitable material require large-scale production such capsules may be printed axially or radially with strengths, methods. The soft gelatin shell is somewhat thicker than that product codes, etc. Pharmaceutical-grade printing inks are us- of hard-shell capsules and may be plasticized by the addition ually based on shellac and employ FDA-approved pigments and of a polyol such as sorbitol or glycerin. The ratio of dry plastici- lake dyes. zer to dry gelatin determines the ‘‘hardness’’ of the shell and In extemporaneous prescription practice, hard-shell capsules may be varied to accommodate environmental conditions as may be hand-filled; this permits the prescriber a latitude of well as the nature of the contents. Like hard shells, the shell choice in selecting either a single drug or a combination of composition may include approved dyes and pigments, opa- drugs at the exact dosage level considered best for the individ- quing agents such as titanium dioxide, and preservatives. Fla- ual patient. This flexibility gives hard-shell capsules an advan- vors may be added and up to 5% sucrose may be included tage over compressed tablets and soft-shell capsules as a for its sweetness and to produce a chewable shell. Soft gelatin dosage form. Hard-shell capsules are usually formed from gela- shells normally contain 6% to 13% water. Soft-shell capsules In-Process Revision
# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1263 also may be printed with a product code, strength, etc. In most CREAMS cases, soft-shell capsules are filled with liquid contents. Typical- ly, active ingredients are dissolved or suspended in a liquid ve- Creams are semisolid dosage forms containing one or more hicle. Classically, an oleaginous vehicle such as a vegetable oil drug substances dissolved or dispersed in a suitable base. This was used; however, nonaqueous, water-miscible liquid vehicles term has traditionally been applied to semisolids that possess a such as the lower-molecular-weight polyethylene glycols are relatively fluid consistency formulated as either water-in-oil more common today due to fewer bioavailability problems. (e.g., Cold Cream) or oil-in-water (e.g., Fluocinolone Acetonide Available in a wide variety of sizes and shapes, soft-shell cap- Cream) emulsions. However, more recently the term has been sules are both formed, filled, and sealed in the same machine; restricted to products consisting of oil-in-water emulsions or typically, this is a rotary die process, although a plate process or aqueous microcrystalline dispersions of long-chain fatty acids reciprocating die process also may be employed. Soft-shell cap- or alcohols that are water washable and more cosmetically sules also may be manufactured in a bubble process that forms and aesthetically acceptable. Creams can be used for adminis- seamless spherical capsules. With suitable equipment, powders tering drugs via the vaginal route (e.g., Triple Sulfa Vaginal and other dry solids also may be filled into soft-shell capsules. Cream). Liquid-filled capsules of either type involve similar formula- tion technology and offer similar advantages and limitations. For instance, both may offer advantages over dry-filled capsules ELIXIRS and tablets in content uniformity and drug dissolution. Greater homogeneity is possible in liquid systems, and liquids can be See Solutions. metered more accurately. Drug dissolution may benefit be- cause the drug may already be in solution or at least suspended in a hydrophilic vehicle. However, the contact between the EMULSIONS hard or soft shell and its liquid content is more intimate than exists with dry-filled capsules, and this may enhance the chanc- Emulsions are two-phase systems in which one liquid is dis- es for undesired interactions. The liquid nature of capsule con- persed throughout another liquid in the form of small droplets. tents presents different technological problems than dry-filled Where oil is the dispersed phase and an aqueous solution is the capsules in regard to disintegration and dissolution testing. continuous phase, the system is designated as an oil-in-water From formulation, technological, and biopharmaceutical emulsion. Conversely, where water or an aqueous solution is points of view, liquid-filled capsules of either type have more the dispersed phase and oil or oleaginous material is the contin- in common than liquid-filled and dry-filled capsules having uous phase, the system is designated as a water-in-oil emulsion. the same shell composition. Thus, for compendial purposes, Emulsions are stabilized by emulsifying agents that prevent co- standards and methods should be established based on capsule alescence, the merging of small droplets into larger droplets contents rather than on whether the contents are filled into and, ultimately, into a single separated phase. Emulsifying hard- or soft-shell capsules. agents (surfactants) do this by concentrating in the interface between the droplet and external phase and by providing a physical barrier around the particle to coalescence. Surfactants DELAYED-RELEASE CAPSULES also reduce the interfacial tension between the phases, thus in- creasing the ease of emulsification upon mixing. Capsules may be coated, or, more commonly, encapsulated Natural, semisynthetic, and synthetic hydrophilic polymers granules may be coated to resist releasing the drug in the gas- may be used in conjunction with surfactants in oil-in-water tric fluid of the stomach where a delay is important to alleviate emulsions as they accumulate at interfaces and also increase potential problems of drug inactivation or gastric mucosal irri- the viscosity of the aqueous phase, thereby decreasing the rate tation. The term ‘‘delayed-release’’ is used for Pharmacopeial of formation of aggregates of droplets. Aggregation is generally monographs on enteric coated capsules that are intended to accompanied by a relatively rapid separation of an emulsion in- delay the release of medicament until the capsule has passed to a droplet-rich and droplet-poor phase. Normally the density through the stomach, and the individual monographs include of an oil is lower than that of water, in which case the oil drop- tests and specifications for Drug release (see Drug Release h724i) lets and droplet aggregates rise, a process referred to as cream- or Disintegration (see Disintegration h701i). ing. The greater the rate of aggregation, the greater the droplet size and the greater the rate of creaming. The water droplets in a water-in-oil emulsion generally sediment because of their EXTENDED-RELEASE CAPSULES greater density. The consistency of emulsions varies widely, ranging from eas- Extended-release capsules are formulated in such manner as ily pourable liquids to semisolid creams. Generally oil-in-water to make the contained medicament available over an extended creams are prepared at high temperature, where they are fluid, period of time following ingestion. Expressions such as ‘‘pro- and cooled to room temperature, whereupon they solidify as a longed-action,’’ ‘‘repeat-action,’’ and ‘‘sustained-release’’ have result of solidification of the internal phase. When this is the also been used to describe such dosage forms. However, the case, a high internal-phase volume to external-phase volume term ‘‘extended-release’’ is used for Pharmacopeial purposes ratio is not necessary for semisolid character, and, for example, and requirements for Drug release (see Drug Release h724i) typ- stearic acid creams or vanishing creams are semisolid with as ically are specified in the individual monographs. little as 15% internal phase. Any semisolid character with wa- ter-in-oil emulsions generally is attributable to a semisolid exter- nal phase. CONCENTRATE FOR DIP All emulsions require an antimicrobial agent because the aqueous phase is favorable to the growth of microorganisms. Concentrate for Dip is a preparation containing one or more The presence of a preservative is particularly critical in oil-in-wa- active ingredients usually in the form of a paste or solution. It is ter emulsions where contamination of the external phase oc- used to prepare a diluted suspension, emulsion, or solution of curs readily. Since fungi and yeasts are found with greater the active ingredient(s) for the prevention and treatment of ec- frequency than bacteria, fungistatic as well as bacteriostatic toparasitic infestations of animals. The diluted preparation properties are desirable. Bacteria have been shown to degrade Revision In-Process (Dip) is applied by complete immersion of the animal or, where nonionic and anionic emulsifying agents, glycerin, and many appropriate, by spraying. Concentrate for Dip may contain suit- natural stabilizers such as tragacanth and guar gum. able antimicrobial preservatives. Complications arise in preserving emulsion systems, as a re- sult of partitioning of the antimicrobial agent out of the aque- ous phase where it is most needed, or of complexation with emulsion ingredients that reduce effectiveness. Therefore, the effectiveness of the preservative system should always be tested
# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1264 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]
in the final product. Preservatives commonly used in emulsions INHALATIONS include methyl-, ethyl-, propyl-, and butyl-parabens, benzoic acid, and quaternary ammonium compounds. Inhalations are drugs or solutions or suspensions of one or See also Creams and Ointments. more drug substances administered by the nasal or oral respi- ratory route for local or systemic effect. Solutions of drug substances in sterile water for inhalation or EXTRACTS AND FLUIDEXTRACTS in sodium chloride inhalation solution may be nebulized by use of inert gases. Nebulizers are suitable for the administration of Extracts are concentrated preparations of vegetable or ani- inhalation solutions only if they give droplets sufficiently fine mal drugs obtained by removal of the active constituents of and uniform in size so that the mist reaches the bronchioles. the respective drugs with suitable menstrua, by evaporation Nebulized solutions may be breathed directly from the nebuliz- of all or nearly all of the solvent, and by adjustment of the re- er or the nebulizer may be attached to a plastic face mask, tent, sidual masses or powders to the prescribed standards. or intermittent positive pressure breathing (IPPB) machine. In the manufacture of most extracts, the drugs are extracted Another group of products, also known as metered-dose in- by percolation. The entire percolates are concentrated, gener- halers (MDIs) are propellant-driven drug suspensions or solu- ally by distillation under reduced pressure in order to subject tions in liquified gas propellant with or without a cosolvent the drug principles to as little heat as possible. and are intended for delivering metered doses of the drug to Fluidextracts are liquid preparations of vegetable drugs, con- the respiratory tract. An MDI contains multiple doses, often ex- taining alcohol as a solvent or as a preservative, or both, and so ceeding several hundred. The most common single-dose vol- made that, unless otherwise specified in an individual mono- umes delivered are from 25 to 100 mL (also expressed as mg) graph, each mL contains the therapeutic constituents of 1 g per actuation. of the standard drug that it represents. Examples of MDIs containing drug solutions and suspensions A fluidextract that tends to deposit sediment may be aged in this pharmacopeia are Epinephrine Inhalation Aerosol and Iso- and filtered or the clear portion decanted, provided the result- proterenol Hydrochloride and Phenylephrine Bitartrate Inhalation ing clear liquid conforms to the Pharmacopeial standards. Aerosol, respectively. Fluidextracts may be prepared from suitable extracts. Powders may also be administered by mechanical devices that require manually produced pressure or a deep inhalation by the patient (e.g., Cromolyn Sodium for Inhalation). GELS A special class of inhalations termed inhalants consists of drugs or combination of drugs, that by virtue of their high va- Gels (sometimes called Jellies) are semisolid systems consist- por pressure, can be carried by an air current into the nasal pas- ing of either suspensions made up of small inorganic particles or sage where they exert their effect. The container from which large organic molecules interpenetrated by a liquid. Where the the inhalant generally is administered is known as an inhaler. gel mass consists of a network of small discrete particles, the gel is classified as a two-phase system (e.g., Aluminum Hydroxide Gel). In a two-phase system, if the particle size of the dispersed INJECTIONS phase is relatively large, the gel mass is sometimes referred to as a magma (e.g., Bentonite Magma). Both gels and magmas may An Injection is a preparation intended for parenteral admin- be thixotropic, forming semisolids on standing and becoming istration or for constituting or diluting a parenteral article prior liquid on agitation. They should be shaken before use to ensure to administration (see Injections h1i). homogeneity and should be labeled to that effect. (See Suspen- Each container of an Injection is filled with a volume in slight sions.) excess of the labeled ‘‘size’’ or that volume that is to be with- Single-phase gels consist of organic macromolecules uni- drawn. The excess volumes recommended in the accompany- formly distributed throughout a liquid in such a manner that ing table are usually sufficient to permit withdrawal and no apparent boundaries exist between the dispersed macro- administration of the labeled volumes. molecules and the liquid. Single-phase gels may be made from synthetic macromolecules (e.g., Carbomer) or from natural gums (e.g., Tragacanth). The latter preparations are also called Recommended Excess Volume mucilages. Although these gels are commonly aqueous, alco- For Mobile For Viscous hols and oils may be used as the continuous phase. For exam- Labeled Size Liquids Liquids ple, mineral oil can be combined with a polyethylene resin to form an oleaginous ointment base. 0.5 mL 0.10 mL 0.12 mL Gels can be used to administer drugs topically or into body 1.0 mL 0.10 mL 0.15 mL cavities (e.g., Phenylephrine Hydrochloride Nasal Jelly). 2.0 mL 0.15 mL 0.25 mL 5.0 mL 0.30 mL 0.50 mL 10.0 mL 0.50 mL 0.70 mL 20.0 mL 0.60 mL 0.90 mL IMPLANTS (PELLETS) 30.0 mL 0.80 mL 1.20 mL 50.0 mL or more 2% 3% Implants or pellets are small sterile solid masses consisting of a highly purified drug (with or without excipients) made by compression or molding. They are intended for implantation in the body (usually subcutaneously) for the purpose of provid- ing continuous release of the drug over long periods of time. IRRIGATIONS Implants are administered by means of a suitable special injec- tor or surgical incision. This dosage form has been used to ad- Irrigations are sterile solutions intended to bathe or flush o- minister hormones such as testosterone or estradiol. They are pen wounds or body cavities. They are used topically, never par- packaged individually in sterile vials or foil strips. enterally. They are labeled to indicate that they are not intended for injection. INFUSIONS, INTRAMAMMARY LOTIONS Intramammary infusions are suspensions of drugs in suitable oil vehicles. These preparations are intended for veterinary use See Solutions or Suspensions. only, and are administered by instillation via the teat canals into the udders of milk-producing animals. In-Process Revision
# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1265
LOZENGES cases, it is necessary to use a base that is less than ideal in order to achieve the stability required. Drugs that hydrolyze rapidly, Lozenges are solid preparations, that are intended to dissolve for example, are more stable in hydrocarbon bases than in ba- or disintegrate slowly in the mouth. They contain one or more ses containing water, even though they may be more effective medicaments, usually in a flavored, sweetened base. They can in the latter. be prepared by molding (gelatin and/or fused sucrose or sorbi- tol base) or by compression of sugar-based tablets. Molded loz- enges are sometimes referred to as pastilles while compressed OPHTHALMIC PREPARATIONS lozenges are often referred to as troches. They are usually in- tended for treatment of local irritation or infections of the Drugs are administered to the eyes in a wide variety of dos- mouth or throat but may contain active ingredients intended age forms, some of which require special consideration. They for systemic absorption after swallowing. are discussed in the following paragraphs.
OINTMENTS Ointments Ointments are semisolid preparations intended for external Ophthalmic ointments are ointments for application to the application to the skin or mucous membranes. eye. Special precautions must be taken in the preparation of Ointment bases recognized for use as vehicles fall into four ophthalmic ointments. They are manufactured from sterilized general classes: the hydrocarbon bases, the absorption bases, ingredients under rigidly aseptic conditions and meet the re- the water-removable bases, and the water-soluble bases. Each quirements under Sterility Tests h71i. If the specific ingredients therapeutic ointment possesses as its base a representative of used in the formulation do not lend themselves to routine ster- one of these four general classes. ilization techniques, ingredients that meet the sterility require- ments described under Sterility Tests h71i, along with aseptic manufacture, may be employed. Ophthalmic ointments must Hydrocarbon Bases contain a suitable substance or mixture of substances to pre- vent growth of, or to destroy, microorganisms accidentally in- These bases, which are known also as ‘‘oleaginous ointment troduced when the container is opened during use, unless bases,’’ are represented by White Petrolatum and White Oint- otherwise directed in the individual monograph, or unless the ment. Only small amounts of an aqueous component can be formula itself is bacteriostatic (see Added Substances under Oph- incorporated into them. They serve to keep medicaments in thalmic Ointments h771i). The medicinal agent is added to the prolonged contact with the skin and act as occlusive dressings. ointment base either as a solution or as a micronized powder. Hydrocarbon bases are used chiefly for their emollient effects, The finished ointment must be free from large particles and and are difficult to wash off. They do not ‘‘dry out’’ or change must meet the requirements for Leakage and for Metal Particles noticeably on aging. under Ophthalmic Ointments h771i. The immediate containers for ophthalmic ointments shall be sterile at the time of filling and closing. It is mandatory that the immediate containers Absorption Bases for ophthalmic ointments be sealed and tamper-proof so that sterility is assured at time of first use. This class of bases may be divided into two groups: the first The ointment base that is selected must be nonirritating to group consisting of bases that permit the incorporation of the eye, permit diffusion of the drug throughout the secretions aqueous solutions with the formation of a water-in-oil emulsion bathing the eye, and retain the activity of the medicament for a (Hydrophilic Petrolatum and Lanolin), and the second group con- reasonable period under proper storage conditions. sisting of water-in-oil emulsions that permit the incorporation Petrolatum is mainly used as a base for ophthalmic drugs. of additional quantities of aqueous solutions (Lanolin). Absorp- Some absorption bases, water-removable bases, and water-sol- tion bases are useful also as emollients. uble bases may be desirable for water-soluble drugs. Such bases allow for better dispersion of water-soluble medicaments, but they must be nonirritating to the eye. Water-Removable Bases Such bases are oil-in-water emulsions, e.g., Hydrophilic Oint- Solutions ment, and are more correctly called ‘‘creams.’’ (See Creams.) They are also described as ‘‘water-washable,’’ since they may Ophthalmic solutions are sterile solutions, essentially free be readily washed from the skin or clothing with water, an at- from foreign particles, suitably compounded and packaged tribute that makes them more acceptable for cosmetic reasons. for instillation into the eye. Preparation of an ophthalmic solu- Some medicaments may be more effective in these bases than tion requires careful consideration of such factors as the inher- in hydrocarbon bases. Other advantages of the water-remov- ent toxicity of the drug itself, isotonicity value, the need for able bases are that they may be diluted with water and that buffering agents, the need for a preservative (and, if needed, they favor the absorption of serous discharges in dermatologi- its selection), sterilization, and proper packaging. Similar con- cal conditions. siderations are also made for nasal and otic products.
Water-Soluble Bases ISOTONICITY VALUE This group of so-called ‘‘greaseless ointment bases’’ compris- Lacrimal fluid is isotonic with blood, having an isotonicity val- es water-soluble constituents. Polyethylene Glycol Ointment is ue corresponding to that of a 0.9% sodium chloride solution. the only Pharmacopeial preparation in this group. Bases of this Ideally, an ophthalmic solution should have this isotonicity val- type offer many of the advantages of the water-removable ba- ue; but the eye can tolerate isotonicity values as low as that of a ses and, in addition, contain no water-insoluble substances 0.6% sodium chloride solution and as high as that of a 2.0% Revision In-Process such as petrolatum, anhydrous lanolin, or waxes. They are more sodium chloride solution without marked discomfort. correctly called ‘‘Gels.’’ (See Gels.) Some ophthalmic solutions are necessarily hypertonic in or- Choice of Base—The choice of an ointment base depends der to enhance absorption and provide a concentration of the upon many factors, such as the action desired, the nature of the active ingredient(s) strong enough to exert a prompt and effec- medicament to be incorporated and its bioavailability and sta- tive action. Where the amount of such solutions used is small, bility, and the requisite shelf-life of the finished product. In some dilution with lacrimal fluid takes place rapidly so that discomfort from the hypertonicity is only temporary. However, any adjust-
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ment toward isotonicity by dilution with tears is negligible PRESERVATION where large volumes of hypertonic solutions are used as collyria to wash the eyes; it is, therefore, important that solutions used Ophthalmic solutions may be packaged in multiple-dose for this purpose be approximately isotonic. containers when intended for the individual use of one patient and where the ocular surfaces are intact. It is mandatory that the immediate containers for ophthalmic solutions be sealed BUFFERING and tamper-proof so that sterility is assured at time of first use. Each solution must contain a suitable substance or mixture Many drugs, notably alkaloidal salts, are most effective at pH of substances to prevent the growth of, or to destroy, microor- levels that favor the undissociated free bases. At such pH levels, ganisms accidentally introduced when the container is opened however, the drug may be unstable so that compromise levels during use. must be found and held by means of buffers. One purpose of Where intended for use in surgical procedures, ophthalmic buffering some ophthalmic solutions is to prevent an increase in solutions, although they must be sterile, should not contain an- pH caused by the slow release of hydroxyl ions by glass. Such a tibacterial agents, since they may be irritating to the ocular tis- rise in pH can affect both the solubility and the stability of the sues. drug. The decision whether or not buffering agents should be added in preparing an ophthalmic solution must be based on several considerations. Normal tears have a pH of about 7.4 and THICKENING AGENT possess some buffer capacity. The application of a solution to the eye stimulates the flow of tears and the rapid neutralization A pharmaceutical grade of methylcellulose (e.g., 1% if the of any excess hydrogen or hydroxyl ions within the buffer capa- viscosity is 25 centipoises, or 0.25% if 4000 centipoises) or oth- city of the tears. Many ophthalmic drugs, such as alkaloidal er suitable thickening agents such as hydroxypropyl methylcel- salts, are weakly acidic and have only weak buffer capacity. lulose or polyvinyl alcohol occasionally are added to Where only 1 or 2 drops of a solution containing them are add- ophthalmic solutions to increase the viscosity and prolong con- ed to the eye, the buffering action of the tears is usually ade- tact of the drug with the tissue. The thickened ophthalmic so- quate to raise the pH and prevent marked discomfort. In lution must be free from visible particles. some cases pH may vary between 3.5 and 8.5. Some drugs, no- tably pilocarpine hydrochloride and epinephrine bitartrate, are more acid and overtax the buffer capacity of the lacrimal fluid. Suspensions Ideally, an ophthalmic solution should have the same pH, as well as the same isotonicity value, as lacrimal fluid. This is not Ophthalmic suspensions are sterile liquid preparations con- usually possible since, at pH 7.4, many drugs are not apprecia- taining solid particles dispersed in a liquid vehicle intended bly soluble in water. Most alkaloidal salts precipitate as the free for application to the eye (see Suspensions). It is imperative that alkaloid at this pH. Additionally, many drugs are chemically un- such suspensions contain the drug in a micronized form to pre- stable at pH levels approaching 7.4. This instability is more vent irritation and/or scratching of the cornea. Ophthalmic sus- marked at the high temperatures employed in heat sterilization. pensions should never be dispensed if there is evidence of For this reason, the buffer system should be selected that is caking or aggregation. nearest to the physiological pH of 7.4 and does not cause pre- cipitation of the drug or its rapid deterioration. An ophthalmic preparation with a buffer system approaching Strips the physiological pH can be obtained by mixing a sterile solu- tion of the drug with a sterile buffer solution using aseptic tech- Fluorescein sodium solution should be dispensed in a sterile, nique. Even so, the possibility of a shorter shelf-life at the higher single-use container or in the form of a sterile, impregnated pa- pH must be taken into consideration, and attention must be di- per strip. The strip releases a sufficient amount of the drug for rected toward the attainment and maintenance of sterility diagnostic purposes when touched to the eye being examined throughout the manipulations. for a foreign body or a corneal abrasion. Contact of the paper Many drugs, when buffered to a therapeutically acceptable with the eye may be avoided by leaching the drug from the pH, would not be stable in solution for long periods of time. strip onto the eye with the aid of sterile water or sterile sodium These products are lyophilized and are intended for reconstitu- chloride solution. tion immediately before use (e.g., Acetylcholine Chloride for Oph- thalmic Solution). PASTES
STERILIZATION Pastes are semisolid dosage forms that contain one or more drug substances intended for topical application. One class is The sterility of solutions applied to an injured eye is of the made from a single-phase aqueous gel (e.g., Carboxymethylce- greatest importance. Sterile preparations in special containers llulose Sodium Paste). The other class, the fatty pastes (e.g., Zinc for individual use on one patient should be available in every Oxide Paste), consists of thick, stiff ointments that do not ordi- hospital, office, or other installation where accidentally or sur- narily flow at body temperature, and therefore serve as protec- gically traumatized eyes are treated. The method of attaining tive coatings over the areas to which they are applied. sterility is determined primarily by the character of the particu- The fatty pastes appear less greasy and more absorptive than lar product (see Sterilization and Sterility Assurance of Compen- ointments by reason of a high proportion of drug substance(s) dial Articles h1211i). having an affinity for water. These pastes tend to absorb serous Whenever possible, sterile membrane filtration under aseptic secretions, and are less penetrating and less macerating than conditions is the preferred method. If it can be shown that pro- ointments, so that they are preferred for acute lesions that have duct stability is not adversely affected, sterilization by autoclav- a tendency towards crusting, vesiculation, or oozing. ing in the final container is also a preferred method. A dental paste is intended for adhesion to the mucous Buffering certain drugs near the physiological pH range membrane for local effect (e.g., Triamcinolone Acetonide Dental makes them quite unstable at high temperature. Paste). Some paste preparations intended for administration to Avoiding the use of heat by employing a bacteria-retaining animals are applied orally. The paste is squeezed into the mouth filter is a valuable technique, provided caution is exercised in of the animal, generally at the back of the tongue, or is spread the selection, assembly, and use of the equipment. Single-filtra- inside the mouth. tion, presterilized disposable units are available and should be utilized wherever possible. In-Process Revision
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PELLETS id dosage forms. For all solutions, but particularly those containing volatile solvents, tight containers, stored away from See Implants. excessive heat, should be used. Consideration should also be given to the use of light-resistant containers when photolytic chemical degradation is a potential stability problem. Dosage POWDERS forms categorized as ‘‘Solutions’’ are classified according to route of administration, such as ‘‘Oral Solutions’’ and ‘‘Topical Powders are intimate mixtures of dry, finely divided drugs Solutions,’’ or by their solute and solvent systems, such as ‘‘Spir- and/or chemicals that may be intended for internal (Oral Pow- its,’’ ‘‘Tinctures,’’ and ‘‘Waters.’’ Solutions intended for paren- ders) or external (Topical Powders) use. Because of their greater teral administration are officially entitled ‘‘Injections’’ (see specific surface area, powders disperse and dissolve more read- Injections h1i). ily than compacted dosage forms. Children and those adults who experience difficulty in swallowing tablets or capsules may find powders more acceptable. Drugs that are too bulky Oral Solutions to be formed into tablets or capsules of convenient size may be administered as powders. Immediately prior to use, oral Oral Solutions are liquid preparations, intended for oral ad- powders are mixed in a beverage or apple sauce. ministration, that contain one or more substances with or with- Often, stability problems encountered in liquid dosage forms out flavoring, sweetening, or coloring agents dissolved in water are avoided in powdered dosage forms. Drugs that are unstable or cosolvent-water mixtures. Oral Solutions may be formulated in aqueous suspensions or solutions may be prepared in the for direct oral administration to the patient or they may be dis- form of granules or powders. These are intended to be consti- pensed in a more concentrated form that must be diluted prior tuted by the pharmacist by the addition of a specified quantity to administration. It is important to recognize that dilution with of water just prior to dispensing. Because these constituted water of Oral Solutions containing cosolvents, such as alcohol, products have limited stability, they are required to have a spec- could lead to precipitation of some ingredients. Hence, great ified expiration date after constitution and may require storage care must be taken in diluting concentrated solutions when co- in a refrigerator. solvents are present. Preparations dispensed as soluble solids or Oral powders may be dispensed in doses premeasured by the soluble mixtures of solids, with the intent of dissolving them in a pharmacist, i.e., divided powders, or in bulk. Traditionally, di- solvent and administering them orally, are designated ‘‘for Oral vided powders have been wrapped in materials such as bond Solution’’ (e.g., Potassium Chloride for Oral Solution). paper and parchment. However, the pharmacist may provide Oral Solutions containing high concentrations of sucrose or greater protection from the environment by sealing individual other sugars traditionally have been designated as Syrups. A doses in small cellophane or polyethylene envelopes. near-saturated solution of sucrose in purified water, for exam- Granules for veterinary use may be administered by sprin- ple, is known as Syrup or ‘‘Simple Syrup.’’ Through common kling the dry powder on animal feed or by mixing it with animal usage the term, syrup, also has been used to include any other food. liquid dosage form prepared in a sweet and viscid vehicle, in- Bulk oral powders are limited to relatively nonpotent drugs cluding oral suspensions. such as laxatives, antacids, dietary supplements, and certain an- In addition to sucrose and other sugars, certain polyols such algesics that the patient may safely measure by the teaspoonful as sorbitol or glycerin may be present in Oral Solutions to inhibit or capful. Other bulky powders include douche powders, tooth crystallization and to modify solubility, taste, mouth-feel, and powders, and dusting powders. Bulk powders are best dis- other vehicle properties. Antimicrobial agents to prevent the pensed in tight, wide-mouth glass containers to afford maxi- growth of bacteria, yeasts, and molds are generally also pre- mum protection from the atmosphere and to prevent the loss sent. Some sugarless Oral Solutions contain sweetening agents of volatile constituents. such as sorbitol or aspartame, as well as thickening agents such Dusting powders are impalpable powders intended for topi- as the cellulose gums. Such viscid sweetened solutions, contain- cal application. They may be dispensed in sifter-top containers ing no sugars, are occasionally prepared as vehicles for admin- to facilitate dusting onto the skin. In general, dusting powders istration of drugs to diabetic patients. should be passed through at least a 100-mesh sieve to assure Many oral solutions, that contain alcohol as a cosolvent, have freedom from grit that could irritate traumatized areas (see been traditionally designated as Elixirs. However, many others Powder Fineness h811i). designated as Oral Solutions also contain significant amounts of alcohol. Since high concentrations of alcohol can produce a pharmacologic effect when administered orally, other cosol- PREMIXES vents, such as glycerin and propylene glycol, should be used to minimize the amount of alcohol required. To be designated Premixes are mixtures of one or more drug substances with as an Elixir, however, the solution must contain alcohol. suitable vehicles. Premixes are intended for admixture to animal feedstuffs before administration. They are used to facilitate di- lution of the active drug components with animal feed. Premix- Topical Solutions es should be as homogeneous as possible. It is essential that materials of suitable fineness be used and that thorough mixing Topical Solutions are solutions, usually aqueous but often be achieved at all stages of premix preparation. Premixes may containing other solvents, such as alcohol and polyols, intend- be prepared as powder, pellets, or in granulated form. The ed for topical application to the skin, or as in the case of Lido- granulated form is free-flowing and free from aggregates. caine Oral Topical Solution, to the oral mucosal surface. The term ‘‘lotion’’ is applied to solutions or suspensions applied topically. SOLUTIONS Otic Solutions Solutions are liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a Otic Solutions, intended for instillation in the outer ear, are suitable solvent or mixture of mutually miscible solvents. Since aqueous, or they are solutions prepared with glycerin or other Revision In-Process molecules in solutions are uniformly dispersed, the use of solu- solvents and dispersing agents (e.g., Antipyrine and Benzocaine tions as dosage forms generally provides for the assurance of Otic Solution and Neomycin and Polymyxin B Sulfates and Hydro- uniform dosage upon administration, and good accuracy when cortisone Otic Solution). diluting or otherwise mixing solutions. Substances in solutions, however, are more susceptible to chemical instability than the solid state and dose for dose, gen- erally require more bulk and weight in packaging relative to sol-
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Ophthalmic Solutions eign odors. Aromatic waters may be prepared by distillation or solution of the aromatic substance, with or without the use of a See Ophthalmic Preparations. dispersing agent. Aromatic waters require protection from intense light and ex- cessive heat. Spirits Spirits are alcoholic or hydroalcoholic solutions of volatile SUPPOSITORIES substances prepared usually by simple solution or by admixture of the ingredients. Some spirits serve as flavoring agents while Suppositories are solid bodies of various weights and shapes, others have medicinal value. Reduction of the high alcoholic adapted for introduction into the rectal, vaginal, or urethral or- content of spirits by admixture with aqueous preparations often ifice of the human body. They usually melt, soften, or dissolve at causes turbidity. body temperature. A suppository may act as a protectant or Spirits require storage in tight, light-resistant containers to palliative to the local tissues at the point of introduction or as prevent loss by evaporation and to limit oxidative changes. a carrier of therapeutic agents for systemic or local action. Sup- pository bases usually employed are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene Tinctures glycols of various molecular weights, and fatty acid esters of polyethylene glycol. Tinctures are alcoholic or hydroalcoholic solutions prepared The suppository base employed has a marked influence on from vegetable materials or from chemical substances. the release of the active ingredient incorporated in it. While co- The proportion of drug represented in the different chemical coa butter melts quickly at body temperature, it is immiscible tinctures is not uniform but varies according to the established with body fluids and this inhibits the diffusion of fat-soluble standards for each. Traditionally, tinctures of potent vegetable drugs to the affected sites. Polyethylene glycol is a suitable base drugs essentially represent the activity of 10 g of the drug in for some antiseptics. In cases where systemic action is expected, each 100 mL of tincture, the potency being adjusted following it is preferable to incorporate the ionized rather than the non- assay. Most other vegetable tinctures represent 20 g of the re- ionized form of the drug, in order to maximize bioavailability. spective vegetable material in each 100 mL of tincture. Although nonionized drugs partition more readily out of water- miscible bases such as glycerinated gelatin and polyethylene glycol, the bases themselves tend to dissolve very slowly and PROCESS P thus retard release in this manner. Oleaginous vehicles such as cocoa butter are seldom used in vaginal preparations be- Carefully mix the ground drug or mixture of drugs with a suf- cause of the nonabsorbable residue formed, while glycerinated ficient quantity of the prescribed solvent or solvent mixture to gelatin is seldom used rectally because of its slow dissolution. render it evenly and distinctly damp, allow it to stand for 15 Cocoa butter and its substitutes (Hard Fat) are superior for allay- minutes, transfer it to a suitable percolator, and pack the drug ing irritation, as in preparations intended for treating internal firmly. Pour on enough of the prescribed solvent or solvent mix- hemorrhoids. ture to saturate the drug, cover the top of the percolator, and, when the liquid is about to drip from the percolator, close the lower orifice and allow the drug to macerate for 24 hours or for Cocoa Butter Suppositories the time specified in the monograph. If no assay is directed, al- low the percolation to proceed slowly, or at the specified rate, Suppositories having cocoa butter as the base may be made gradually adding sufficient solvent or solvent mixture to pro- by means of incorporating the finely divided medicinal sub- duce 1000 mL of tincture, and mix (for definitions of flow rates, stance into the solid oil at room temperature and suitably shap- see under Extracts and Fluidextracts). If an assay is directed, col- ing the resulting mass, or by working with the oil in the melted lect only 950 mL of percolate, mix this, and assay a portion of it state and allowing the resulting suspension to cool in molds. A as directed. Dilute the remainder with such quantity of the pre- suitable quantity of hardening agents may be added to coun- scribed solvent or solvent mixture as calculation from the assay teract the tendency of some medicaments such as chloral hy- indicates is necessary to produce a tincture that conforms to the drate and phenol to soften the base. It is important that the prescribed standard, and mix. finished suppository melt at body temperature. The approximate weights of suppositories prepared with co- coa butter are given below. Suppositories prepared from other PROCESS M bases vary in weight and generally are heavier than the weights indicated here. Macerate the drug with 750 mL of the prescribed solvent or Rectal Suppositories for adults are tapered at one or both ends solvent mixture in a container that can be closed, and put in a and usually weigh about 2 g each. warm place. Agitate it frequently during 3 days or until the sol- Vaginal Suppositories are usually globular or oviform and uble matter is dissolved. Transfer the mixture to a filter, and weigh about 5 g each. They are made from water-soluble or wa- when most of the liquid has drained away, wash the residue ter-miscible vehicles such as polyethylene glycol or glycerinated on the filter with a sufficient quantity of the prescribed solvent gelatin. or solvent mixture, combining the filtrates, to produce 1000 mL Suppositories with cocoa butter base require storage in well- of tincture, and mix. closed containers, preferably at a temperature below 308 (con- Tinctures require storage in tight, light-resistant containers, trolled room temperature). away from direct sunlight and excessive heat.
Cocoa Butter Substitutes Waters, Aromatic Fat-type suppository bases can be produced from a variety of Aromatic waters are clear, saturated aqueous solutions (un- vegetable oils, such as coconut or palm kernel, which are mod- less otherwise specified) of volatile oils or other aromatic or vol- ified by esterification, hydrogenation, and fractionation to ob- atile substances. Their odors and tastes are similar, respectively, tain products of varying composition and melting temperatures to those of the drugs or volatile substances from which they are (e.g., Hydrogenated Vegetable Oil and Hard Fat). These products prepared, and they are free from empyreumatic and other for- can be so designed as to reduce rancidity. At the same time, desired characteristics such as narrow intervals between melt- In-Process Revision
# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1269 ing and solidification temperatures, and melting ranges to ac- otic administration. These may be of two types, ready to use or commodate various formulation and climatic conditions, can intended for constitution with a prescribed amount of Water for be built in. Injection or other suitable diluent before use by the designated route. Suspensions should not be injected intravenously or in- trathecally. Glycerinated Gelatin Suppositories Suspensions intended for any route of administration should contain suitable antimicrobial agents to protect against bacte- Medicinal substances may be incorporated into glycerinated ria, yeast, and mold contamination (see Emulsions for some gelatin bases by addition of the prescribed quantities to a vehi- consideration of antimicrobial preservative properties that ap- cle consisting of about 70 parts of glycerin, 20 parts of gelatin, ply also to Suspensions). By its very nature, the particular matter and 10 parts of water. in a suspension may settle or sediment to the bottom of the Glycerinated gelatin suppositories require storage in tight container upon standing. Such sedimentation may also lead containers, preferably at a temperature below 358. to caking and solidification of the sediment with a resulting dif- ficulty in redispersing the suspension upon agitation. To pre- vent such problems, suitable ingredients that increase Polyethylene Glycol–Base Suppositories viscosity and the gel state of the suspension, such as clays, sur- factants, polyols, polymers, or sugars, should be added. It is im- Several combinations of polyethylene glycols having melting portant that suspensions always be shaken well before use to temperatures that are above body temperature have been used ensure uniform distribution of the solid in the vehicle, thereby as suppository bases. Inasmuch as release from these bases de- ensuring uniform and proper dosage. Suspensions require stor- pends on dissolution rather than on melting, there are signifi- age in tight containers. cantly fewer problems in preparation and storage than exist with melting-type vehicles. However, high concentrations of higher-molecular-weight polyethylene glycols may lengthen Oral Suspensions dissolution time, resulting in problems with retention. Labels on polyethylene glycol suppositories should contain directions Oral Suspensions are liquid preparations containing solid par- that they be moistened with water before inserting. Although ticles dispersed in a liquid vehicle, with suitable flavoring they can be stored without refrigeration, they should be pack- agents, intended for oral administration. Some suspensions la- aged in tightly closed containers. beled as ‘‘Milks’’ or ‘‘Magmas’’ fall into this category.
Surfactant Suppository Bases Topical Suspensions Several nonionic surface-active agents closely related chemi- Topical Suspensions are liquid preparations containing solid cally to the polyethylene glycols can be used as suppository ve- particles dispersed in a liquid vehicle, intended for application hicles. Examples of such surfactants are polyoxyethylene to the skin. Some suspensions labeled as ‘‘Lotions’’ fall into this sorbitan fatty acid esters and the polyoxyethylene stearates. category. These surfactants are used alone or in combination with other suppository vehicles to yield a wide range of melting tempera- tures and consistencies. One of the major advantages of such Otic Suspensions vehicles is their water-dispersibility. However, care must be tak- en with the use of surfactants, because they may either increase Otic Suspensions are liquid preparations containing micron- the rate of drug absorption or interact with drug molecules, ized particles intended for instillation in the outer ear. causing a decrease in therapeutic activity. Ophthalmic Suspensions Tableted Suppositories or Inserts See Ophthalmic Preparations. Vaginal suppositories occasionally are prepared by the com- pression of powdered materials into a suitable shape. They are prepared also by encapsulation in soft gelatin. SYRUPS See Oral Solutions. SUSPENSIONS Suspensions are liquid preparations that consist of solid par- SYSTEMS ticles dispersed throughout a liquid phase in which the particles are not soluble. Dosage forms officially categorized as ‘‘Suspen- In recent years, a number of dosage forms have been devel- sions’’ are designated as such if they are not included in other oped using modern technology that allows for the uniform re- more specific categories of suspensions, such as Oral Suspen- lease or targeting of drugs to the body. These products are sions, Topical Suspensions, etc. (see these other categories). commonly called delivery systems. The most widely used of Some suspensions are prepared and ready for use, while others these are Transdermal Systems. are prepared as solid mixtures intended for constitution just be- fore use with an appropriate vehicle. Such products are desig- nated ‘‘for Oral Suspension’’, etc. The term ‘‘Milk’’ is sometimes Transdermal Systems used for suspensions in aqueous vehicles intended for oral ad- ministration (e.g., Milk of Magnesia). The term ‘‘Magma’’ is of- Transdermal drug delivery systems are self-contained, dis- ten used to describe suspensions of inorganic solids such as crete dosage forms that, when applied to intact skin, are de- Revision In-Process clays in water, where there is a tendency for strong hydration signed to deliver the drug(s) through the skin to the systemic and aggregation of the solid, giving rise to gel-like consistency circulation. Systems typically comprise an outer covering (bar- and thixotropic rheological behavior (e.g., Bentonite Magma). rier), a drug reservoir, which may have a rate-controlling The term ‘‘Lotion’’ has been used to categorize many topical membrane, a contact adhesive applied to some or all parts of suspensions and emulsions intended for application to the skin the system and the system/skin interface, and a protective liner (e.g., Calamine Lotion). Some suspensions are prepared in sterile that is removed before applying the system. The activity of form and are used as Injectables, as well as for ophthalmic and
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these systems is defined in terms of the release rate of the gredients and formerly were intended for use in making pre- drug(s) from the system. The total duration of drug release from parations for hypodermic injection. They are employed orally, the system and the system surface area may also be stated. or where rapid drug availability is required such as in the case Transdermal drug delivery systems work by diffusion: the of Nitroglycerin Tablets, sublingually. drug diffuses from the drug reservoir, directly or through the Buccal tablets are intended to be inserted in the buccal rate-controlling membrane and/or contact adhesive if present, pouch, and sublingual tablets are intended to be inserted be- and then through the skin into the general circulation. Typical- neath the tongue, where the active ingredient is absorbed di- ly, modified-release systems are designed to provide drug deliv- rectly through the oral mucosa. Few drugs are readily absorbed ery at a constant rate, such that a true steady-state blood in this way, but for those that are (such as nitroglycerin and cer- concentration is achieved and maintained until the system is re- tain steroid hormones), a number of advantages may result. moved. At that time, blood concentration declines at a rate Soluble, effervescent tablets are prepared by compression consistent with the pharmacokinetics of the drug. and contain, in addition to active ingredients, mixtures of acids Transdermal drug delivery systems are applied to body areas (citric acid, tartaric acid) and sodium bicarbonate, which re- consistent with the labeling for the product(s). As long as drug lease carbon dioxide when dissolved in water. They are intend- concentration at the system/skin interface remains constant, ed to be dissolved or dispersed in water before administration. the amount of drug in the dosage form does not influence plas- Effervescent tablets should be stored in tightly closed con- ma concentrations. The functional lifetime of the system is de- tainers or moisture-proof packs and labeled to indicate that fined by the initial amount of drug in the reservoir and the they are not to be swallowed directly. release rate from the reservoir. NOTE—Drugs for local rather than systemic effect are com- monly applied to the skin embedded in glue on a cloth or plas- Chewable Tablets tic backing. These products are defined traditionally as plasters or tapes. Chewable tablets are formulated and manufactured so that they may be chewed, producing a pleasant tasting residue in the oral cavity that is easily swallowed and does not leave a bit- Ocular System ter or unpleasant aftertaste. These tablets have been used in tablet formulations for children, especially multivitamin formu- Another type of system is the ocular system, which is intend- lations, and for the administration of antacids and selected an- ed for placement in the lower conjunctival fornix from which tibiotics. Chewable tablets are prepared by compression, the drug diffuses through a membrane at a constant rate usually utilizing mannitol, sorbitol, or sucrose as binders and fil- (e.g., Pilocarpine Ocular System). lers, and containing colors and flavors to enhance their appear- ance and taste. Intrauterine System Preparation of Molded Tablets An intrauterine system, based on a similar principle but in- tended for release of drug over a much longer period of time, Molded tablets are prepared from mixtures of medicinal sub- e.g., one year, is also available (e.g., Progesterone Intrauterine stances and a diluent usually consisting of lactose and pow- Contraceptive System). dered sucrose in varying proportions. The powders are dampened with solutions containing high percentages of alco- hol. The concentration of alcohol depends upon the solubility TABLETS of the active ingredients and fillers in the solvent system and the desired degree of hardness of the finished tablets. The damp- Tablets are solid dosage forms containing medicinal sub- ened powders are pressed into molds, removed, and allowed stances with or without suitable diluents. They may be classed, to dry. Molded tablets are quite friable and care must be taken according to the method of manufacture, as compressed tab- in packaging and dispensing. lets or molded tablets. The vast majority of all tablets manufactured are made by compression, and compressed tablets are the most widely used Formulation of Compressed Tablets dosage form in this country. Compressed tablets are prepared by the application of high pressures, utilizing steel punches and Most compressed tablets consist of the active ingredient and dies, to powders or granulations. Tablets can be produced in a a diluent (filler), binder, disintegrating agent, and lubricant. Ap- wide variety of sizes, shapes, and surface markings, depending proved FD&C and D&C dyes or lakes (dyes adsorbed onto in- upon the design of the punches and dies. Capsule-shaped tab- soluble aluminum hydroxide), flavors, and sweetening agents lets are commonly referred to as caplets. Boluses are large tab- may also be present. Diluents are added where the quantity lets intended for veterinary use, usually for large animals. of active ingredient is small or difficult to compress. Common Molded tablets are prepared by forcing dampened powders tablet fillers include lactose, starch, dibasic calcium phosphate, under low pressure into die cavities. Solidification depends up- and microcrystalline cellulose. Chewable tablets often contain on crystal bridges built up during the subsequent drying pro- sucrose, mannitol, or sorbitol as a filler. Where the amount of cess, and not upon the compaction force. active ingredient is small, the overall tableting properties are Tablet triturates are small, usually cylindrical, molded or com- in large measure determined by the filler. Because of problems pressed tablets. Tablet triturates were traditionally used as dis- encountered with bioavailability of hydrophobic drugs of low pensing tablets in order to provide a convenient, measured water-solubility, water-soluble diluents are used as fillers for quantity of a potent drug for compounding purposes. Such these tablets. tablets are rarely used today. Hypodermic tablets are molded tablets made from completely and readily water-soluble in- In-Process Revision
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Binders give adhesiveness to the powder during the prelimi- Physical evidence of poor tablet quality is discussed under nary granulation and to the compressed tablet. They add to the Stability Considerations in Dispensing Practice h1191i. cohesive strength already available in the diluent. While binders may be added dry, they are more effective when added out of solution. Common binders include acacia, gelatin, sucrose, po- WEIGHT VARIATION AND CONTENT UNIFORMITY vidone, methylcellulose, carboxymethylcellulose, and hydro- lyzed starch pastes. The most effective dry binder is Tablets are required to meet a weight variation test (see Uni- microcrystalline cellulose, which is commonly used for this pur- formity of Dosage Units h905i) where the active ingredient com- pose in tablets prepared by direct compression. prises a major portion of the tablet and where control of weight A disintegrating agent serves to assist in the fragmentation of may be presumed to be an adequate control of drug content the tablet after administration. The most widely used tablet dis- uniformity. Weight variation is not an adequate indication of integrating agent is starch. Chemically modified starches and content uniformity where the drug substance comprises a rela- cellulose, alginic acid, microcrystalline cellulose, and cross- tively minor portion of the tablet, or where the tablet is sugar- linked povidone, are also used for this purpose. Effervescent coated. Thus, the Pharmacopeia generally requires that coated mixtures are used in soluble tablet systems as disintegrating tablets and tablets containing 50 mg or less of active ingredi- agents. The concentration of the disintegrating agent, method ent, comprising less than 50% by weight of the dosage-form of addition, and degree of compaction play a role in effective- unit, pass a content uniformity test (see Uniformity of Dosage ness. Units h905i), wherein individual tablets are assayed for actual Lubricants reduce friction during the compression and ejec- drug content. tion cycle. In addition, they aid in preventing adherence of tab- let material to the dies and punches. Metallic stearates, stearic acid, hydrogenated vegetable oils, and talc are used as lubri- DISINTEGRATION AND DISSOLUTION cants. Because of the nature of this function, most lubricants are hydrophobic, and as such tend to reduce the rates of tablet Disintegration is an essential attribute of tablets intended for disintegration and dissolution. Consequently, excessive con- administration by mouth, except for those intended to be centrations of lubricant should be avoided. Polyethylene glycols chewed before being swallowed and for some types of extend- and some lauryl sulfate salts have been used as soluble lubri- ed-release tablets. A disintegration test is provided (see Disinte- cants, but such agents generally do not possess optimal lubri- gration h701i), and limits on the times in which disintegration is cating properties, and comparatively high concentrations are to take place, appropriate for the types of tablets concerned, usually required. are given in the individual monographs. Glidants are agents that improve powder fluidity, and they For drugs of limited water-solubility, dissolution may be a are commonly employed in direct compression where no gran- more meaningful quality attribute than disintegration. A disso- ulation step is involved. The most effective glidants are the col- lution test (see Dissolution h711i) is required in a number of loidal pyrogenic silicas. monographs on tablets. In many cases, it is possible to correlate Colorants are often added to tablet formulations for esthetic dissolution rates with biological availability of the active ingre- value or for product identification. Both D&C and FD&C dyes dient. However, such tests are useful mainly as a means of and lakes are used. Most dyes are photosensitive and they fade screening preliminary formulations and as a routine quality- when exposed to light. The federal Food and Drug Administra- control procedure. tion regulates the colorants employed in drugs.
Coatings Manufacturing Methods Tablets may be coated for a variety of reasons, including pro- Tablets are prepared by three general methods: wet granula- tection of the ingredients from air, moisture, or light, masking tion, dry granulation (roll compaction or slugging), and direct of unpleasant tastes and odors, improvement of appearance, compression. The purpose of both wet and dry granulation is to and control of the site of drug release in the gastrointestinal improve flow of the mixture and/or to enhance its compressi- tract. bility. Dry granulation (slugging) involves the compaction of pow- ders at high pressures into large, often poorly formed tablet PLAIN COATED TABLETS compacts. These compacts are then milled and screened to form a granulation of the desired particle size. The advantage Classically, tablets have been coated with sugar applied from of dry granulation is the elimination of both heat and moisture aqueous suspensions containing insoluble powders such as in the processing. Dry granulations can be produced also by ex- starch, calcium carbonate, talc, or titanium dioxide, suspended truding powders between hydraulically operated rollers to pro- by means of acacia or gelatin. For purposes of identification and duce thin cakes which are subsequently screened or milled to esthetic value, the outside coatings may be colored. The fin- give the desired granule size. ished coated tablets are polished by application of dilute solu- Excipients are available that allow production of tablets at tions of wax in solvents such as chloroform or powdered mix. high speeds without prior granulation steps. These directly Water-protective coatings consisting of substances such as shel- compressible excipients consist of special physical forms of sub- lac or cellulose acetate phthalate are often applied out of non- stances such as lactose, sucrose, dextrose, or cellulose, which aqueous solvents prior to application of sugar coats. Excessive possess the desirable properties of fluidity and compressibility. quantities should be avoided. Drawbacks of sugar coating in- The most widely used direct-compaction fillers are microcrystal- clude the lengthy time necessary for application, the need for line cellulose, anhydrous lactose, spray-dried lactose, compress- waterproofing, which also adversely affects dissolution, and the ible sucrose, and some forms of modified starches. Direct increased bulk of the finished tablet. These factors have resulted compression avoids many of the problems associated with in increased acceptance of film coatings. Film coatings consist wet and dry granulations. However, the inherent physical pro- of water-soluble or dispersible materials such as hydroxypropyl perties of the individual filler materials are highly critical, and methylcellulose, methylcellulose, hydroxypropylcellulose, car- minor variations can alter flow and compression characteristics boxymethylcellulose sodium, and mixtures of cellulose acetate Revision In-Process so as to make them unsuitable for direct compression. phthalate and polyethylene glycols applied out of nonaqueous or aqueous solvents. Evaporation of the solvents leaves a thin film that adheres directly to the tablet and allows it to retain the original shape, including grooves or identification codes.
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DELAYED-RELEASE TABLETS A dosage form is a combination of drug substances Where the drug may be destroyed or inactivated by the gas- and excipients to facilitate dosing, administration, and tric juice or where it may irritate the gastric mucosa, the use of ‘‘enteric’’ coatings is indicated. Such coatings are intended to delivery of the medicine to the patient. The design and delay the release of the medication until the tablet has passed through the stomach. The term ‘‘delayed-release’’ is used for testing of all dosage forms target drug product quality.1 Pharmacopeial purposes, and the individual monographs in- clude tests and specifications for Drug release (see Drug Release A testing protocol must consider not only the physical, h724i)orDisintegration (see Disintegration h701i). chemical, and biological properties of the dosage form
EXTENDED-RELEASE TABLETS as appropriate but also the administration route and de- Extended-release tablets are formulated in such manner as to sireddosingregimen.Theinterrelationships of dosage make the contained medicament available over an extended period of time following ingestion. Expressions such as ‘‘pro- forms and routes of administration have been summa- longed-action,’’ ‘‘repeat-action,’’ and ‘‘sustained-release’’ have also been used to describe such dosage forms. However, the rized in the compendial taxonomy for pharmaceutical term ‘‘extended-release’’ is used for Pharmacopeial purposes, and requirements for Drug release typically are specified in the dosage forms (Figure 1).2 The organization of this general individual monographs. information chapter is by the physical attributes of each particular dosage form (Tier Two), generally without spe- &GENERAL CONSIDERATIONS cific reference to route of administration. Information specific to route of administration is given when needed. This chapter provides general descriptions of and def- Tests to ensure compliance with pharmacopeial stan- initions for drug products, or dosage forms, commonly dards for dosage form performance fall into one of the used to administer the drug substance [active pharma- following areas. ceutical ingredient (API)]. It discusses general principles involved in the manufacture or compounding of these dosage forms, and recommendations for proper use and storage. A glossary is provided as a resource on no- menclature.
1 In the United States, a drug with a name recognized in USP– NF must comply with compendial identity standards or be deemed adulterated, misbranded, or both. To avoid being deemed adulterated, such drugs also must comply with com- pendial standards for strength, quality, or purity, unless labeled to show all respects in which the drug differs. See the Federal Food, Drug, and Cosmetic Act (FDCA), Sections 501(b) and 502(e)(3)(b), and Food and Drug Administration (FDA) regu- lations at 21 CFR 299.5. In addition, to avoid being deemed misbranded, drugs recognized in USP–NF also must comply with compendial standards for packing and labeling, FDCA Sec- tion 502(g). ‘‘Quality’’ is used herein as suitable shorthand for all such compendial requirements. This approach also is consis- tent with U.S. and FDA participation in the International Con- ference on Harmonization (ICH). The ICH guideline on specifications, Q6A, notes that ‘‘specifications are chosen to confirm the quality of the drug substance and drug product. . .’’ and defines ‘‘quality’’ as ‘‘The suitability of either a drug sub- stance or drug product for its intended use. This term includes such attributes as identity, strength, and purity.’’ 2 Marshall K, Foster TS, Carlin HS, Williams RL. Development of a compendial taxonomy and glossary for pharmaceutical dos- age forms. Pharm Forum. 2003;29(5):1742–1752. In-Process Revision
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Dose Uniformity (see also Uniformity of Dosage Units forms requires careful evaluation of drug substance par- h905i)—Consistency in dosing for a patient or consumer ticle or droplet size, incorporation techniques, and excip- requires that the variation in the drug substance content ient properties. of each dosage unit be accurately controlled throughout Stability (see also Pharmaceutical Stability h1150i)— the manufactured batch or compounded lot of drug pro- Drug product stability involves the evaluation of chemi- duct. Uniformity of dosage units typically is demonstra- cal stability, physical stability, and performance over ted by one of two procedures: content uniformity or time. The chemical stability of the drug substance in weight variation. The procedure for content uniformity the dose form matrix must support the expiration dating requires the assay of drug substance content of individual for the commercially prepared dosage forms and a be- units, and that for weight variation uses the weight of the yond-use date for a compounded dosage form. Test pro- individual units to estimate their content. Weight varia- cedures for potency must be stability indicating (see tion may be used where the underlying distribution of Validation of Compendial Procedures h1225i). Degrada- drug substance in the blend is presumed to be uniform tion products should be quantified. In the case of dis- and well-controlled, as in solutions. In such cases the persed or emulsified systems, consideration must be content of drug substance may be adequately estimated given to the potential for settling or separation of the for- by the net weight. Content uniformity does not rely on mulation components. Any physical changes to the dos- the assumption of blend uniformity and can be applied in age form must be easily reversed (e.g., by shaking) prior all cases. Tablets and capsules are assigned a limit below to dosing or administration. In vitro release test proce- nPoesRevision In-Process which the weight variation procedure is not applicable. dures such as dissolution and disintegration provide a Successful development and manufacture of dosage measure of continuing consistency in performance over time (see Dissolution h711i, Disintegration h701i,and Drug Release h724i).
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route of administration (e.g., by injection—Particulate Bioavailability (see also In Vitro and In Vivo Evaluation Matter in Injections h788i, or mucosal—Particulate Matter of Dosage Forms h1088i, and Assessment of Drug Product in Ophthalmic Solutions h789i). Additionally, dosage Performance—Bioavailability, Bioequivalence, and Dissolu- forms intended for the inhalation route of administration tion h1090i)—Bioavailability is influenced by factors such must be monitored for particle size and spray pattern (for as the method of manufacture or compounding, particle a metered-dose inhaler or dry-powder inhaler) and drop- size, crystal form (polymorph) of the drug substance, the let size (for nasal sprays). Further information regarding properties of the excipients used to formulate the dosage administration routes and suggested testing can be form, and physical changes as the drug product ages. As- found in the Guide to General Chapters, Charts 4–8 and surance of consistency in bioavailability over time (bio- 10–13. equivalence) requires close attention to all aspects of An appropriate manufacturing process and testing re- the production (or compounding) and testing of the gimen help ensure that a dosage form can meet the ap- dosage form. In vitro release (disintegration and dissolu- propriate quality attributes for the intended route of tion) testing is commonly used as a surrogate to demon- administration. strate consistent availability of the API from the formulated dosage. PRODUCT QUALITY TESTS, GENERAL Manufacture—Although detailed instructions about the manufacture of any of these dosage forms are be- ICH Guidance Q6A (available at www.ich.org) recom- yond the scope of this general information chapter, gen- mends specifications (list of tests, references to analytical eral manufacturing principles have been included, as well procedures, and acceptance criteria) to ensure that com- as suggested testing for proper use and storage. Further mercialized drug products are safe and effective at the information relative to extemporaneous compounding time of release and over their shelf life. Tests that are uni- of dosage forms can be found in Pharmaceutical Com- versally applied to ensure safety and efficacy (and pounding—Nonsterile Preparations h795i and Pharmaceu- strength, quality, and purity) include description, identi- tical Compounding—Sterile Preparations h797i. fication, assay, and impurities. Route of Administration—The primary routes of Description—According to the ICH guidance a qual- administration for pharmaceutical dosage forms can be itative description (size, shape, color, etc.) of the dosage defined as mucosal, oral, parenteral (by injection), inha- form should be provided. The acceptance criteria should lation, and topical/dermal, and each has subcategories include the final acceptable appearance. If any of these as needed. Many tests employed to ensure quality gen- characteristics change during manufacturing or storage, erally are applied across all of the administration routes, a quantitative procedure may be appropriate. It specifies but some tests are specific for individual routes. For ex- the content or the label claim of the article. This param- ample, products intended for injection must be evaluat- eter is not part of the USP dosage form monograph be- ed for Sterility h71i and Pyrogen Test h151i,andthe cause it is product specific. USP monographs define the manufacturing process (and sterilization technique) em- product by specifying the range of acceptable assayed ployed for parenterals (by injection) should ensure com- content of the active substance(s) present in the dosage pliance with these tests. Tests for particulate matter may form, together with any additional information about be required for solution dosage forms depending on the the presence or absence of other components, excipi- ents, or adjuvants. In-Process Revision
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evaluated by tests in API and excipients monographs. Im- Identification—Identification tests are discussed in purities arising from degradation of the drug substance the General Notices and Requirements. Identification tests or from the drug-product manufacturing process should should establish the identity of the drug or drugs present be monitored. Residual Solvents h467i is applied to all in the drug product and should discriminate between products where relevant. compounds of closely related structure that are likely to In addition to the universal tests listed above, the fol- be present. Identification tests should be specific for the lowing tests may be considered on a case-by-case basis. drug substances. The most conclusive test for identity is Physicochemical Properties—Examples include pH the infrared absorption spectrum (see Spectrophotometry h791i, Viscosity h911i, and Specific Gravity h841i. and Light-Scattering h851i and Spectrophotometric Identi- Particle Size—Forsomedosageforms,particlesize fication Tests h197i). If no suitable infrared spectrum can can have a significant effect on dissolution rates, bioavail- be obtained, other analytical methods can be used. ability, therapeutic outcome, and stability. Procedures Near-infrared (NIR) or Raman spectrophotometric meth- such as Aerosols, Nasal Sprays, Metered-Dose Inhalers, ods also could be acceptable as the sole identification and Dry Powder Inhalers h601i, and Particle Size Distribu- method of the drug product formulation (see Near- tion Estimation by Analytical Sieving h786i could be used. infrared Spectrophotometry h1119i and Raman Spectrosco- py h1120i). Identification by a chromatographic reten- Uniformity of Dosage Units—See discussion of tion time from a single procedure is not regarded as dose uniformity above. specific. The use of retention times from two chromato- Water Content—A test for water content is included graphic procedures for which the separation is based on when appropriate (see Water Determination h921i). different principles or a combination of tests in a single Microbial Limits—The type of microbial test(s) and procedure can be acceptable (see Chromatography acceptance criteria are based on the nature of the drug h621i and Thin-Layer Chromatographic Identification Test substance, method of manufacture, and the route of ad- h201i). ministration (see Microbiological Examination of Nonsterile
Assay—A specific and stability-indicating test should Products: Microbial Enumeration Tests h61i and Microbio- be used to determine the strength (API content) of the logical Examination of Nonsterile Products: Tests for Speci- drug product. Some examples of these procedures are fied Microorganisms h62i). Antibiotics—Microbial Assays h81i, Chromatography Antimicrobial Preservative Content—Accep- h621i,orAssay for Steroids h351i. In cases when the use tance criteria for preservative content in multidose prod- of a nonspecific assay is justified, e.g., Titrimetry h541i, ucts should be established. They are based on the levels other supporting analytical procedures should be used of antimicrobial preservative necessary to maintain the to achieve specificity. When evidence of excipient inter- product’s microbiological quality at all stages through- ference with a nonspecific assay exists, a procedure with out its proposed usage and shelf life (see Antimicrobial Ef- demonstrated specificity should be used. fectiveness Testing h51i).
Impurities—Process impurities, synthetic by- Antioxidant Preservative Content—If antioxidant Revision In-Process products, and other inorganic and organic impurities preservatives are present in the drug product, tests of may be present in the API and excipients used in the their content should be performed. manufacture of the drug product. These impurities are
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DOSAGE FORMS Sterility—Depending on the route of administra- tion—e.g., ophthalmic preparations, implants, and solu- Aerosols tions for injection—sterility of the product is demonstrated as appropriate (see Sterility Tests h71i). Aerosols are preparations packaged under pressure and contain therapeutic agent(s) and a propellant that Dissolution—A test to measure release of the drug are released upon activation of an appropriate valve sys- substance(s) from the drug product normally is included tem. Upon activation of the valve system, the drug sub- for dosage forms such as tablets, capsules, suspensions, stance is released as a plume of fine particles or droplets. granules for suspensions, implants, transdermal delivery Only one dose is released from the preparation upon ac- systems, and medicated chewing gums. Single-point tivation of a metered valve. In the case of topical prod- measurements typically are used for immediate-release ucts, activation of the valve results in a continuous dosage forms. For modified-release dosage forms, appro- release of the formulation. priate test conditions and sampling procedures are es- In this chapter, the aerosol dosage form refers only to tablished as needed (see Dissolution h711i and Drug those products packaged under pressure that release a Release h724i). In some cases, dissolution testing may fine mist of particles or droplets when activated (see Glos- be replaced by disintegration testing (see Disintegration sary). Other products that produce dispersions of fine h701i). droplets or particles will be covered in subsequent sec- Hardness and Friability—These parameters are tions (e.g., Dry Powder Inhalers and Sprays). evaluated as in-process controls. Acceptance criteria de- pend on packaging, supply chain, and intended use (see
Tablet Friability h1216i and Tablet Breaking Force h1217i). TYPICAL COMPONENTS Extractables—When evidence exists that extracta- Typical components of aerosols are the formulation bles from the container-closure systems (e.g., rubber containing one or more drug substances and propellant, stopper, cap liner, or plastic bottle) have an impact on the container, the valve, and the actuator. Each compo- the safety or efficacy of the drug product, a test is includ- nent plays a role in determining various characteristics of ed to evaluate the presence of extractables and leach- the emitted plume, such as droplet or particle size distri- ables. bution, uniformity of delivery of the therapeutic agent, Depending on the type and composition of the dosage delivery rate, and plume velocity and geometry. The me- form, other tests such as alcohol content, redispersibility, tering valve and actuator act in tandem to generate the particle size distribution, rheological properties, reconsti- plume of droplets or particles. The metering valve allows tution time, endotoxins/pyrogens, particulate matter, measure of an accurate volume of the liquid formulation functionality testing of delivery systems, and osmolarity under pressure within the container. The activator directs may be necessary. the metered volume to a small orifice that is open to the atmosphere. Upon activation, the formulation is forced through the opening, forming the fine mist of particles that are directed to the site of administration. In-Process Revision
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Aerosol preparations may consist of either a two-phase Inhalation aerosols are intended to produce fine parti- (gas and liquid) or a three-phase (gas, liquid, and solid or cles or droplets for inhalation through the mouth and de- liquid) formulation. The two-phase formulation consists position in the pulmonary tree. The design of the delivery of drug(s) dissolved in liquefied propellant. Liquid co- system releases one dose with each actuation. These solvents, such as alcohol, propylene glycol, and polyeth- products are commonly known as metered-dose inhal- ylene glycols often are added to enhance the solubility of ers. the drug substance(s). Three phase inhalation and nasal Nasal aerosols produce fine particles or droplets for in- aerosol systems consist of a suspension or emulsion of halation through the nasal vestibule and deposition in the drug substance(s) [i.e., API(s)] in addition to the va- the nasal cavity. One dose is released with each activation porizable propellants. The suspension or emulsion of the of the valve. finely divided drug substance typically is dispersed in the Lingual aerosols are intended to produce fine particles liquid propellant with the aid of suitable biocompatible or droplets for deposition in the mouth. The design of surfactants or other excipients. the delivery system releases one dose with each actua- Propellants for aerosol formulations are typically low tion. molecular weight hydrofluorocarbons or hydrocarbons Topical aerosols produce fine particles or droplets for that are liquid when constrained in the container, exhibit application to the skin. Formulations that are intended a suitable vapor pressure at room temperature, and are for inhalation, nasal, or lingual administration are typical- biocompatible and nonirritating. Compressed gases do ly aqueous based, but topical aerosols may utilize nonaq- not supply a constant pressure over use and typically ueous solvents to achieve rapid drying or disinfectant are not employed as propellants. action for abraded skin surfaces. Metal containers can withstand the vapor pressure produced by the propellant and reduce the opportunity PACKAGING that leachable components will enter the formulation. Excess formulation may be added to the container to en- The accuracy of a system’s delivered dose is demon- sure that the full number of labeled doses can be ac- strated at the range of pressures likely to be encountered curately administered. The container and closure must as a result of ambient temperature variations or storage be able to withstand the pressures anticipated under nor- in a refrigerator. As an alternative, the system should in- mal use conditions as well as when the system is exposed clude clear instructions for use to ensure the container to elevated temperatures. and contents have been equilibrated to room tempera- ture prior to use.
TYPES OF AEROSOL DOSAGE FORMS
LABELING FOR PROPER USE Aerosol dosage forms can be delivered via various routes. The design of the container and metering valve, Typical warning statements include:
as well as the formulation, are designed to target the site Contents under pressure. Do not puncture or incin- Revision In-Process of administration. erate container. Do not expose to heat or store at temperatures above 498.
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